myelin

Posted on Multiple Sclerosis

Multiple Sclerosis -Strategies for the regeneration of myelin

Impaired repair of chronic lesions in NcKO


Impaired repair of chronic lesions in neuronal cholesterol mutants (NcKO). The mutants form less myelin (brown), and the proliferation of oligodendrocytes (green) is reduced. CREDIT MPI for Experimental Medicine/ Berghoff

The degradation and regeneration of myelin sheaths characterise neurological disorders such as multiple sclerosis. Cholesterol is an indispensable component of myelin sheaths. The cholesterol for the regenerated myelin sheaths must therefore either be recycled from damaged myelin or produced again locally. In a recent study, scientists at the Max Planck Institute for Experimental Medicine in Göttingen, led by Gesine Saher, found that in the case of chronic damage, unlike in acute damage, hardly any cholesterol is recycled. Instead, the new production of cholesterol determines the efficiency of the repair. Unexpectedly, not only the myelin-forming cells themselves but also nerve cells make an important contribution to regeneration. Cholesterol synthesis in nerve cells ensures the replenishment of newly myelin-forming cells. This could impact the therapeutic success for myelin disorders such as multiple sclerosis.

When lesions develop in myelin disorders such as multiple sclerosis, the cholesterol- and lipid-rich insulating layer around the nerve fibres is lost. In order to prevent permanent damage, the now unmyelinated nerve fibres must be protected again as quickly as possible by newly regenerated myelin. In the acute phase of the disorder, defective myelin is abundant. Cholesterol is taken up from defective myelin by phagocytes and reprocessed and made available to the myelin-forming cells. This repair process often proceeds quickly and smoothly in younger patients.

However, the longer the disorder lasts, the less efficient this critical process becomes. Phagocytes of the brain can turn into foam cells that are no longer involved in the recycling of cholesterol. The chronic and repeated degradation of myelin sheaths eventually leaves nerve fibres permanently unmyelinated. Degenerated myelin and cholesterol are thus scarce in chronic lesions. “We suspected that in the low-cholesterol environment of chronic lesions, the production of this important lipid kicks in”, explains lead researcher Gesine Saher from the Max Planck Institute for Experimental Medicine in Göttingen.

Cholesterol from nerve cells promotes the regeneration of myelin-forming cells

Saher and her working group are investigating the role of cholesterol and other lipids in the nervous system under both physiological and pathological conditions. Together with an international team of researchers, they have now investigated which of the body’s own processes contribute to repair after chronic myelin disease.

In their study, the researchers examined nerve cells (neurons) from pharmacological and genetic mouse models with myelin defects. Neurons normally cover the majority of their cholesterol demand by uptake of lipid-rich lipoproteins with only little synthesis. In acute lesions, cholesterol production in nerve cells is even further reduced. “The fact that the neurons from the chronic disorder models boost the production of cholesterol was completely surprising”, reports Stefan Berghoff, former coworker of Gesine Saher and first author of the study.

In order to investigate the relevance of this observation, the researchers genetically inactivated the synthesis of cholesterol in neurons and in the myelin-forming cells (oligodendrocytes) of mice. In the neuronal and oligodendroglial mutants, the regeneration of myelin sheaths was severely reduced in chronic lesions. However, unlike in glial mutants, neuronal cholesterol also enhanced the proliferation of oligodendrocyte progenitor cells. Treatment with a cholesterol-enriched diet had a similarly positive effect on these progenitor cells. “We assume that neurons provide this extra production of cholesterol”, says Berghoff. “This benefits all other cells in chronic lesions, which have greatly reduced their own production of cholesterol”.

Although acute and chronic lesions and their endogenous repair mechanisms differ greatly, the availability and management of cholesterol and other lipids ultimately makes a considerable contribution to the efficiency of regeneration. “The challenge of the next studies will be to develop therapy concepts for patients with myelin disorders in which acute and chronic lesions can be treated simultaneously”, says Saher, leader of the research team.

Posted on Multiple Sclerosis

UCalgary scientists discover a new way to battle multiple sclerosis




 




University of Calgary scientists Andrew Caprariello, Ph.D., left, and Dr. Peter Stys, professor at the Cumming School of Medicine, are challenging conventional thinking about the root cause of multiple sclerosis. Cumming School of Medicine

Ridiculous. That’s how Andrew Caprariello says his colleagues described his theory about multiple sclerosis (MS) back when he was doing his PhD in Ohio.

Caprariello’s passion to explore controversial new theories about MS propelled him to seek out a postdoctoral fellowship with a like-minded thinker, whom he found in University of Calgary’s Dr. Peter Stys, a member of the Hotchkiss Brain Institute at the Cumming School of Medicine(CSM).

The collaboration paid off. Caprariello, Stys and their colleagues have scientific proof published in the Proceedings of the National Academy of Sciences (PNAS) that their somewhat radical theory has merit. “I’ve always wondered ‘what if’ MS starts in the brain and the immune attacks are a consequence of the brain damage,” says Caprariello, PhD, and lead author on the study.




Currently, MS is considered to be a progressive autoimmune disease. Brain inflammation happens when the body’s immune system attacks a protective material around nerve fibers in the brain called myelin. Conventional thinking is that rogue immune cells initially enter the brain and cause myelin damage that starts MS.

“In the field, the controversy about what starts MS has been brewing for more than a decade. In medical school, I was taught years ago that the immune attack initiates the disease. End of story,” says Stys, a neurologist and professor in the Department of Clinical Neurosciences at the CSM. “However, our findings show there may be something happening deeper and earlier that damages the myelin and then later triggers the immune attacks.”

To test the theory, the research team designed a mouse model of MS that begins with a mild myelin injury. In this way, researchers could mirror what they believe to be the earliest stages of the disease.

“Our experiments show, at least in this animal model, that a subtle early biochemical injury to myelin secondarily triggers an immune response that leads to additional damage due to inflammation. It looks very much like an MS plaque on MRI and tissue examination,” says Stys. “This does not prove that human MS advances in the same way, but provides compelling evidence that MS could also begin this way.”

With that result, the researchers started to investigate treatments to stop the degeneration of the myelin to see if that could reduce, or stop, the secondary autoimmune response.

“We collaborated with researchers at the University of Toronto and found that by targeting a treatment that would protect the myelin to stop the deterioration, the immune attack stopped and the inflammation in the brain never occurred,” says Stys. “This research opens a whole new line of thinking about this disease. Most of the science and treatment for MS has been targeted at the immune system, and while anti-inflammatory medications can be very effective, they have very limited benefit in the later progressive stages of the disease when most disability happens.”

It can be very hard to find funding to investigate an unconventional theory. The research team was funded by the Brain and Mental Health Strategic Research Fund, established by the Office of the Vice-President (Research) at UCalgary to support innovative, interdisciplinary studies within the Brain and Mental Health research strategy.

“We chose high-risk, novel projects for these funds to support discoveries by teams who did not have the chance to work together through conventional funding sources,” said Ed McCauley, PhD, vice-president (research). “The MS study shows the potential of brain and mental health scholars to expand capacity by tapping into new approaches for conducting research. Their work also exemplifies the type of interdisciplinary research that is propelling the University of Calgary as an international leader in brain and mental health research.”